Chronic methionine (MET) stress, defined as depletion of plasma MET to levels below 5 microM, can be induced in animals with withdrawal of dietary MET, homocysteine (HCYS), and choline (CHOL) plus periodic administration of recombinant L-methionine-alpha-deamino-gamma-lyase (rMETase) and rescue homocystine (HCYSS), given i.p. every 8 and 24 h, respectively. This study describes the effect of this MET depleting regimen (METdr) on normal and malignant tissue using athymic mice bearing human glial tumor xenografts. A 7-day METdr in athymic mice bearing SWB40 and U87 anaplastic astrocytoma xenografts reduced tumor MET to 30% of their baseline values. Although this reduction halted tumor growth, it did not induce the expected complete inhibition of mitosis or a rapid and extensive necrosis. In contrast, SWB77 and D-54 xenografts (glioblastomas) showed marked regression, widespread necrosis, and complete loss of mitotic activity when they were subjected to METdr. Levels of MET in SWB77 and D-54 did not respond to METdr as readily as those in SWB40 and U87 and remained relatively high as the tumor responded to treatment and regressed. High steady states of MET along with the absence of HCYS in high-grade gliomas indicates that transmethylation reactions may be inhibited in such tumors under modest methionine stress conditions. On the basis of these results, it is postulated that METdr in its present formulation is more effective against high-grade, more aggressive gliomas, which are resistant to chemotherapy, than against the more differentiated astrocytic tumors. This may be due to the higher requirements of high-grade gliomas for MET to maintain a state of active proliferation. Further studies are needed to identify the source of MET in glial tumors under METdr and to develop more effective regimens to deplete tumor MET, which might result in a complete and sustained regression of high-grade gliomas.